The re-emergence of TB as a world-wide health problem has been complicated by the increasing prevalence of drug-resistant M. tuberculosis. The goals of the proposed research are to investigate the molecular basis for resistance to ethambutol and isoniazid, and to define the cell wall biosynthetic pathways inhibited by these drugs. The molecular and classical genetic analyses of resistance genes and the study of resistance mechanisms are ultimately directed at identifying key biosynthetic enzymes as targets for new drug development. Our efforts will be aided by our recent success with this approach in the study of ethambutol resistance in Mycobacterim avium.